Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction

Abstract

Abstract. Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

“…Simvastatin was shown to induce caspase-dependent apoptosis in A549 cells which is regulated by the Bcl2 family proteins and ROS and can be reversed by treatment with N-acetylcysteine4647. Other investigators have reported that simvastatin can induce apoptotic pathways in A549 and H460 cells by blocking the cell cycle and down-regulating cyclin D1 and cyclin dependent kinases (CDKs) expression4849.…”

Drug repurposing in malignant pleural mesothelioma: a breath of fresh air?

“…In addition, the combination of lovastatin and valproate was shown to reduce cell invasion of Acc-Meso-1, a human-derived MPM cell line [110]. HWANG et al [51] reported a synergistic effect of the combination of pemetrexed and simvastatin on apoptosis induction in MSTO-211 MPM cells by reactive oxygen [43] Inhibition of angiogenesis [44] Inhibition of invasion and metastasis [45] Induction of tumour differentiation [46] Reversion of multidrug resistance [47] Phase III: gastric cancer [48], colorectal cancer [49] Phase III: ongoing in SCLC [50] Preclinical [47,[51][52][53] Itraconazole Antifungal Induction of angiogenesis [54] Inhibition of hedgehog pathway [8] Phase II: NSCLC [55] Prostate cancer [56] Basal cell carcinoma [57] Preclinical [58] Arsenic trioxide Preclinical [52,85,88] Thalidomide Sickness in pregnant females (withdrawn) [29] Inhibition of angiogenesis [31] Inhibition of cell proliferation [32] Immunomodulatory function [33] FDA approved: multiple myeloma [34] Phase III [37] Anisomycin Antibiotic Induction of apoptosis [89] Preclinical [90] Preclinical [90]…”

Reactive oxygen species a double-edged sword for mesothelioma

“…Pemetrexed induces caspase-dependent and -independent apoptosis in human melanoma cells through intracellular ROS accumulation, which in turn promotes DNA damage [ 169 ]. In MM cell lines, pemetrexed induced ROS production and caspase-dependent apoptosis [ 170 ]. To the best of our knowledge, no previous study has investigated on ROS production in mesotlelioma cells upon pemetrexed and cisplatin combination treatment.…”